Absolute Configuration Of Chiral Molecules Research Articles

Polyarylisocyanides Derived from an Alkyne-Pd(II) Catalyst as Robust Alignment Media with Excellent Enantiodiscimination.

The development of chiral alignment media for measuring anisotropic NMR parameters provides an opportunity to determine the absolute configuration of chiral molecules without the need for derivatization. However, chiral alignment media with a high and robust enantiodiscriminating property for a wide range of chiral molecules are still scarce. In this study, we synthesized cholesterol-end-functionalized helical polyisocyanides from a chiral monomer using a cholesterol-based alkyne-Pd(II) initiator. These stereoregular polyisocyanides form stable and weak anisotropic lyotropic liquid crystals (LLCs) in dichloromethane systems, exhibiting highly optical activities in both single left- and right-handed helices. The preparation process of the media was straightforward, and the aligning property of the LLCs could be controlled by adjusting the concentration and temperature. Using the chiral polyisocyanides, we extracted the residual dipolar coupling for an enantiomeric pair of isopinocampheol (IPC), as well as a number of pharmaceutical molecules, demonstrating excellent enantiodiscriminating properties for a broad range of chiral compounds.

An Artificial Intelligence Approach for Tackling Conformational Energy Uncertainties in Chiroptical Spectroscopies.

Determination of the absolute configuration of chiral molecules is a prerequisite for obtaining a fundamental understanding in any chirality-related field. The interaction with polarised light has proven to be a powerful means to determine this absolute configuration, but its application rests on the comparison between experimental and computed spectra for which the inherent uncertainty in conformational Boltzmann factors has proven to be extremely hard to tackle. Here we present a novel approach that overcomes this issue by combining a genetic algorithm that identifies the relevant conformers by accounting for the uncertainties in DFT relative energies, and a hierarchical clustering algorithm that analyses the trends in the spectra of the considered conformers and identifies on-the-fly when a given chiroptical technique is not able to make reliable predictions. The effectiveness of this approach is demonstrated by considering the challenging cases of papuamine and haliclonadiamine, two bis-indane natural products with eight chiral centres and considerable conformational heterogeneity that could not be assigned unambiguously with current approaches.

An Artificial Intelligence Approach for Tackling Conformational Energy Uncertainties in Chiroptical Spectroscopies

AbstractDetermination of the absolute configuration of chiral molecules is a prerequisite for obtaining a fundamental understanding in any chirality‐related field. The interaction with polarised light has proven to be a powerful means to determine this absolute configuration, but its application rests on the comparison between experimental and computed spectra for which the inherent uncertainty in conformational Boltzmann factors has proven to be extremely hard to tackle. Here we present a novel approach that overcomes this issue by combining a genetic algorithm that identifies the relevant conformers by accounting for the uncertainties in DFT relative energies, and a hierarchical clustering algorithm that analyses the trends in the spectra of the considered conformers and identifies on‐the‐fly when a given chiroptical technique is not able to make reliable predictions. The effectiveness of this approach is demonstrated by considering the challenging cases of papuamine and haliclonadiamine, two bis‐indane natural products with eight chiral centres and considerable conformational heterogeneity that could not be assigned unambiguously with current approaches.

The Story Behind the Link between Molecular Chirality and Crystal Shape

AbstractHere we describe the story behind the link between molecular chirality and macroscopic phenomena, the latter being a probe for the direct assignment of absolute configuration of chiral molecules. First, a brief tour of the history of molecular stereochemistry, starting with the classic experiment reported byPasteurin 1848 on the separation of enantiomorphous crystals of a salt of tartaric acid, and his conclusion that the molecules of life are chiral of single‐handedness. With time, this study raised, inter alia, two fundamental questions: the absolute configuration of chiral molecules and how a molecule of given configuration shapes the enantiomorphous morphology of its crystal. As for the first question, following the beginning of crystal structure determination by X‐ray diffraction in 1912, it took almost 40 years beforeBijvoetassigned molecular chirality through the esoteric method involving anomalous X‐ray scattering. We have been able to address and link both questions through ‘everyday concepts of left and right’ (in the words ofJack Dunitz) by the use of ‘tailor‐made’ auxiliaries. By such means, it proved possible to reveal, through morphology, etch patterns, epitaxy and symmetry reduction of both chiral and, paradoxically, centrosymmetric crystals, the basic chiral symmetry of the molecules of life, the α‐amino acids and sugars.

Discrimination of Aluminum from Silicon by Electron Crystallography with the JUNGFRAU Detector

The crystal structure of a chemical compound serves several purposes: its coordinates represent three-dimensional information about the connectivity between the atoms; it is the only technique that determines the absolute configuration of chiral molecules; it enables determining structure–function relations; and crystallographic data at atomic resolution distinguish between element types and serve as a confirmation of synthesis protocols. Here, we collected electron diffraction data from albite and from a Linde Type A (LTA) type zeolite. Both compounds are aluminosilicates with well-defined silicon and aluminum crystallographic sites. Data were recorded with the “adJUstiNg Gain detector FoR the Aramis User station” (JUNGFRAU detector) and we made use of its capability of energy discrimination to suppress noise. For both compounds, crystallographic refinement distinguishes correctly between silicon and aluminum, even though these elements have very similar electron scattering factors. These results highlight the quality of the electron diffraction data and the reliability of the models for chemical interpretation. Further development in this direction will provide enormous opportunities for structure–function studies by diffraction.

Absolute Configuration of Small Molecules by Co‐Crystallization

AbstractThe most reliable method to determine the absolute configuration of chiral molecules is X‐ray crystallography, but small molecules can be difficult to crystallize. We report rapid co‐crystallization of tetraaryladamantanes with small molecules as different as n‐decane to nicotine to produce crystals for X‐ray analysis and the assignment of absolute configuration when the molecules are chiral. A screen of 52 diverse compounds gave inclusion in co‐crystals for 88 % of all cases and a high‐resolution structure in 77 % of cases. Furthermore, starting from three milligrams of analyte, a combination of NMR spectroscopy and X‐ray crystallography produced a full structure in less than three days using an adamantane crystallization chaperone that encapsulates the analyte at room temperature.

Absolute Configuration of Small Molecules by Co-Crystallization.

The most reliable method to determine the absolute configuration of chiral molecules is X‐ray crystallography, but small molecules can be difficult to crystallize. We report rapid co‐crystallization of tetraaryladamantanes with small molecules as different as n‐decane to nicotine to produce crystals for X‐ray analysis and the assignment of absolute configuration when the molecules are chiral. A screen of 52 diverse compounds gave inclusion in co‐crystals for 88 % of all cases and a high‐resolution structure in 77 % of cases. Furthermore, starting from three milligrams of analyte, a combination of NMR spectroscopy and X‐ray crystallography produced a full structure in less than three days using an adamantane crystallization chaperone that encapsulates the analyte at room temperature.

Determination of Absolute Stereochemistry of Flexible Molecules Using a Vibrational Circular Dichroism Spectra Alignment Algorithm.

Experimental determination of the absolute stereochemistry of chiral molecules has been a fundamental challenge in natural sciences for decades. Vibrational circular dichroism (VCD) spectroscopy represents an attractive alternative to traditional methods like X-ray crystallography due to the use of molecules in solution. The interpretation of measured VCD spectra and thus the assignment of the absolute configuration relies on quantum-mechanical calculations. While such calculations are straightforward for rigid molecules with a single conformation, the need to estimate the correct conformational ensemble and energy landscape to obtain the appropriate theoretical spectra poses significant challenges for flexible molecules. In this work, we present the development of a VCD spectra alignment (VSA) algorithm to compare theoretical and experimental VCD spectra. The algorithm determines which enantiomer is more likely to reproduce the experimental spectrum and thus allows the correct assignment of the absolute stereochemistry. The VSA algorithm is successfully applied to determine the absolute chirality of highly flexible molecules, including commercial drug substances. Furthermore, we show that the computational cost can be reduced by performing the full frequency calculation only for a reduced set of conformers. The presented approach has the potential to allow the determination of the absolute configuration of chiral molecules in a robust and efficient manner.

Absolute configurations of chiral molecules with multiple stereogenic centers without prior knowledge of the relative configurations: A case study of inuloxin C.

AbstractElectronic circular dichroism (ECD) and discrete wavelength resolved specific optical rotations, referred to as optical rotatory dispersion (ORD), have been remeasured for inuloxin C and analysed with corresponding quantum chemical (QC) predicted data for all diastereomers of inuloxin C. The QC‐predicted sign of ORD and of a major ECD band are found to match the experimental observations for more than one diastereomer. However, these ECD and ORD analyses combined with electronic dissymmetry factor analyses narrowed the choices of absolute configuration (AC) of inuloxin C to (5R,7S,8R,10R) and (5S,7S,8S,10S). Supplementing these analyses with corresponding analyses for acetylated inuloxin C resulted in a unique choice for the AC of inuloxin C as (5S,7S,8S,10S). This result is independent of NMR analysis. Furthermore, this AC is in full agreement with previously determined relative configuration by NMR and the AC derived therefrom using ECD and ORD. Therefore, the present study identifies a pathway for determining the ACs of chiral molecules with multiple stereogenic centers when relative configurations are not known, or when it is desired to deduce ACs independent of the known relative configurations.

Investigating Absolute Stereochemical Configuration with Coulomb Explosion Imaging.

It is a particularly challenging task in stereochemistry to determine the absolute configuration of chiral molecules, i.e. to assign to a given sample the microscopic enantiomeric structure. In recent years, Coulomb Explosion Imaging (CEI) has been shown to yield directly the absolute configuration of small molecules in the gas phase. This contribution describes the experimental basics of this approach, highlights the most significant results and discusses limitations. A short discussion on extending Coulomb Explosion Imaging beyond analytic aspects to fundamental questions of molecular chirality concludes this review.

Chiral Molecular Science: How were the absolute configurations of chiral molecules determined? "Experimental results and theories".

Molecular chirality is a key concept in chemistry, bioscience, and molecular technology, like the invention of a light-powered chiral molecular motor explained in this review. Thus, the primary research subject is how to determine the absolute configuration (AC) of chiral compounds. This review article focuses on the principle, theory, and practice of the nonempirical methods for determining ACs of chiral compounds, i.e., the Bijvoet method in X-ray crystallography and the circular dichroism (CD) exciton chirality method, together with the historical aspects of AC determination. The theoretical equations of X-ray crystallography and exciton CD spectroscopy are explained in detail, and these equations are useful for readers to understand the principle and mechanism of these methods. This review also focuses on the relative methods, where the internal reference with known AC is used and the relative configuration is determined by X-ray crystallography and/or 1 H nuclear magnetic resonance (NMR) diamagnetic anisotropy method. In these cases, CSDP acid and MαNP acid are useful for the chiral resolution of racemic alcohols, where their diastereomeric esters are easily separable by high-performance liquid chromatography (HPLC) on silica gel. Thus, these methods are useful for the preparation of enantiopure compounds and simultaneous determination of their ACs. In this review article, the above methods are explained mainly based on the author's own research results.

Optical Rotation Calculations for Fluorinated Alcohols, Amines, Amides, and Esters.

We have calculated the optical rotation at λ = 589 nm for 45 fluorinated alcohols, amines, amides, and esters using both time-dependent density functional theory (TDDFT) with the CAM-B3LYP functional and the second-order approximate coupled-cluster singles and doubles (CC2) method, where the aug-cc-pVDZ basis set was adopted in both methods. Comparison of CAM-B3LYP and CC2 results to experiments illustrates that both methods are able to reproduce the experimental optical rotation results for both sign and magnitude. Several conformers for molecules containing the benzyloxy and naphthalene groups needed to be considered to obtain consistent signs with experiments, and these conformers are discussed in detail. We have also used a two-point inverse power extrapolation of the basis set to investigate the optical rotation in the basis set limit at the CC2 level, however, we only found small differences compared to the aug-cc-pVTZ results. Our results demonstrate that the least computationally expensive method investigated here, the CAM-B3LYP functional with the aug-cc-pVDZ basis set, is a reliable method to predict the optical rotation for large molecules and thereby the absolute configuration of chiral molecules.

ChemInform Abstract: Assignment of Absolute Stereostructures Through Quantum Mechanics Electronic and Vibrational Circular Dichroism Calculations

AbstractReview: 58 refs.

Synthesis of Cryptochiral (R,R)‐2,3‐Dideuterooxirane as Stereochemical Reference Compound and Chemical Correlation with D‐(+)‐Glyceraldehyde

AbstractChirality plays a pivotal role in chemistry and biology, e.g., structure‐specific targeting in drug development or the lock‐and‐key theory of enzyme interactions. Determining absolute configurations of chiral molecules is essential to understanding such mechanisms and to developing chemical processes involving chiral compounds. In particular, this becomes obvious in the understanding of chemical reaction networks in the context of the origins of life. A stereochemical reference compound that can be correlated with sugars, amino acids, etc. is of great interest. Here, we present the synthesis of enantiopure (R,R)‐2,3‐dideuterooxirane, of which the absolute configuration has been unambiguously determined by foil‐induced Coulomb explosion imaging, and the correlation with the configuration of D‐(+)‐glyceraldehyde.

Communication: Probing the absolute configuration of chiral molecules at aqueous interfaces.

We demonstrate that the enantiomers of chiral macromolecules at an aqueous interface can be distinguished with monolayer sensitivity using heterodyne-detected vibrational sum-frequency generation (VSFG). We perform VSFG spectroscopy with a polarization combination that selectively probes chiral molecular structures. By using frequencies far detuned from electronic resonances, we probe the chiral macromolecular structures with high surface specificity. The phase of the sum-frequency light generated by the chiral molecules is determined using heterodyne detection. With this approach, we can distinguish right-handed and left-handed helical peptides at a water-air interface. We thus show that heterodyne-detected VSFG is sensitive to the absolute configuration of complex, interfacial macromolecules and has the potential to determine the absolute configuration of enantiomers at interfaces.

Using laser-induced Coulomb explosion of aligned chiral molecules to determine their absolute configuration

The absolute configuration of chiral molecules in the gas phase is determined by femtosecond laser-induced Coulomb explosion and recording of the emission direction of critical ionic fragments. The spatial orientation of the 3,5-dibromo-3′,5′-diflouro-4′-cyanobiphenyl molecules studied is determined by a combination of laser-induced alignment and time-of-flight measurement of F+ ion recoils. Hereby, the enatiomeric state of the molecules could be uniquely identified through analysis of the correlation of the angular distribution of F+ and Br+ ions. The method will apply to a range of molecules and allow imaging of chiral changes on ultrafast time scales.

Synthesis and Stereochemical Assignment of Crypto‐Optically Active 2H6‐Neopentane

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of (2) H6 -1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to (2) H6 -1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

ChemInform Abstract: Determination of Absolute Configuration by 31P NMR

AbstractReview: 55 refs.

Implementation of the CCSD-PCM linear response function for frequency dependent properties in solution: Application to polarizability and specific rotation

This work reports the first implementation of the frequency dependent linear response (LR) function for the coupled cluster singles and doubles method (CCSD) combined with the polarizable continuum model of solvation for the calculation of frequency dependent properties in solution. In particular, values of static and dynamic polarizability as well as specific rotation are presented for various test molecules. Model calculations of polarizability show that a common approximation used in the definition of the LR function with solvation models recovers over 70% of the full response while maintaining a computational cost comparable to gas phase LR-CCSD. Calculations of specific rotation for three compounds for which gas phase methods predict the wrong sign of the rotation show that accounting for the electronic response of the solvent may be essential to assign the correct absolute configuration of chiral molecules.

FICA, a new chiral derivatizing agent for determining the absolute configuration of secondary alcohols by 19F and 1H NMR spectroscopies

Optically active 1-fluoroindan-1-carboxylic acid (FICA) was designed and prepared as its methyl ester for determining the absolute configuration of chiral molecules by both 1H and 19F NMR spectroscopies. Enantiomerically pure isomers of FICA methyl esters (FICA Me esters) were obtained by chromatographic separation using HPLC with a Daicel Chiralcel OJ-H column. The absolute configuration of the (+)-FICA Me ester was deduced to be (S) by X-ray crystallographic analysis of the (+)-FICA amide of (R)-α-phenethylamine. Both enantiomers were derived to the diastereomeric esters of chiral secondary alcohols by an ester exchange reaction. In the 1H NMR spectra, the signs of ΔδH (δR−δS) were consistent on each side of the FICA molecular plane. Therefore, the concept of the modified Mosher’s method could be successfully applied to the FICA-based procedure. Moreover, the consistency in the signs of ΔδF (δR−δS) values suggests that the FICA method would be reliable in assigning the absolute configurations of secondary alcohols based on 19F NMR spectroscopy.